Low-Dose Rabbit Antithymocyte Globulin Induction Therapy Results in Prolonged Selective Lymphocyte Depletion Irrespective of Maintenance Immunosuppression

Abstract

Rabbit antithymocyte globulin therapy (rATG) is a potent lymphocyte-depleting agent commonly used following renal transplantation to reduce the risk of acute rejection. Standard doses (7–10 mg/kg) of rATG result in profound lymphopenia and predispose patients to infection and malignancy. The effects of lower doses of rATG (LoD-rATG, 3–5 mg/kg) on peripheral blood lymphocytes (PBL) are as yet unknown. In this prospective clinical trial, PBL subsets were characterized by flow cytometry over 12 months following LoD-rATG therapy. All patients were initially treated with standard doses of tacrolimus, mycophenolic acid, and prednisone. At 3 months, patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence. LoD-rATG therapy resulted in prolonged suppression of CD19 + B cells, total CD3 + T cells, as well as naïve and memory CD4 + T cell and CD4/CD25/Foxp3 + T-regulatory subsets irrespective of chronic immunosuppressive therapy. Selective depletion was only noted in the CD4CD45RA + naïve T-cell subset resulting in an altered memory/naïve CD4 + ratio. LoD-rATG failed to deplete CD8 + T cells, which increased their relative contribution to the total CD3 + pool. All other lymphocyte subsets maintained near normal proportions. Thus, LoD-rATG therapy may lessen the adverse effects of full dose rATG while maintaining overall efficacy.